The recent withdrawal of dexfenfluramine (DFEN) from the market has left many obese individuals and their clinicians without effective pharmacological tools. Behavioral programs (e.g., diet, exercise) alone have notoriously poor records of long-term success in combating obesity. The most popular and apparently effective drug regimen prior to the withdrawal was phentermine (PHEN) and DFEN. It is important to understand why the DFEN/PHEN combination was so effective, and to use this information to drive drug discovery programs and treatment regimens. Astonishingly, there is little available animal literature on the behavioral efficacy of DFEN/PHEN, data that would form the foundation of assessing combination effects. Three main studies are proposed in this revised application. First, an isobolographic analysis of whether DFEN/PHEN's anorectic effects are simply dose-additive of each drug or are supra-additive (implying a synergistic mechanism). The second study is a pharmacological study of the mechanisms of the combination using selective adrenergic and serotonergic antagonists. The third proposed study will investigate the sites of action of the combination in the brain using Fos immunoreactivity as an index of neural activation. Potentially, these results will provide useful information toward the future development of more effective anorectics. On a broader level, examining the combined effects of anorectics that target different transmitter systems represents a useful model for evaluating how neurotransmitters interact to control feeding behavior.